It’s no surprise that drugs don’t always play together nicely in the human body. The term “drug interaction” can stir up a great deal of fear in unsuspecting healthcare consumers and, as a result, a number of web-based drug interaction cross checking systems have been made available to help spread awareness of the risks of combining certain drugs. Drugs change the chemical landscape of the body, and these changes can impact how additional drugs affect the body in both favorable and unfavorable ways. These interactions can occur both at the drug’s pharmacological targets as well as the metabolic pathways which convert drugs to their metabolites. Perhaps the most common source of drug interactions is the cytochrome P450 oxidase system of enzymes which serve to detoxify foreign substances called xenobiotics.1 Xenobiotics are the so-called “stranger molecules” which can include drugs along with chemicals found in the diet that are not native to the human body. A majority of these molecules are degraded by the liver through a series of metabolic pathways.
Drug metabolism occurs in a series of phases. These conversions divert the drug molecule away from its target organs and allow it to be more readily eliminated from the body through the kidneys. Phase I of the process modifies the starting structure in subtle ways which make the molecule more polar and more conducive to further modification.2 These reactions are commonly oxidation-reduction type reactions which usually terminate the drug’s mechanism of action and facilitate additional structural changes. Occasionally, a Phase I reaction may convert an inactive drug into an active drug or an active drug into an even more active drug. However, the outcome is almost always a molecule of greater polarity which can be more readily excreted or further modified. Phase II reactions conjugate (link) the modified form with polar, charged, or bulky molecules like glucuronic acid or glutathione which enhance the molecule’s water solubility and impair membrane permeability.3 If the product of a Phase I reaction is not soluble enough to be excreted, a Phase II conjugation reaction will typically accomplish this. These Phase II conjugates can be thought of as having chemical labeling tags which notify cells that the molecule is to be disposed of. After Phase II, a final Phase III process can modify these xenobiotic conjugates in ways that enhance the linker molecule’s attraction for transport proteins which pump the metabolite out of the cell.4 While this may all seem complex, the net effect of the entire process is to transform a drug molecule into a less active yet more bulky and water-soluble metabolite which can be easily excreted.
All phases of this overall process are facilitated by enzymes. The family of enzymes responsible for mediating Phase I is known as the cytochrome P450 (CYP450) oxidase system, a vast group of over 50 different enzymes which all carry out a unique type of metabolic reaction on a unique type of xenobiotic.5 These enzymes are also able to carry out metabolic reactions on many chemicals which occur naturally in the human body including cholesterol, fatty acids, and hormones. The nature of the reaction varies from enzyme to enzyme, with some P450 enzymes being very specific and others being somewhat more versatile. Phase II and Phase III are carried out by a much more generalized group of transferase and peptidase enzymes which do not exhibit the same degree of specificity as CYP450 enzymes.2 Being an enzymatic process, drug metabolism as a whole is highly susceptible to competition, inhibition, and induction. Inhibition slows the degradation of drugs while induction effectively hastens the process.5 These are the precise phenomena which are responsible for a majority of commonly encountered drug interactions.
Of all the different CYP450 enzymes, four are responsible for the metabolic degradation of a majority of psychiatric drugs. These include CYP1A2, CYP2C19, CYP2D6, and CYP3A4. CYP3A4 alone accounts for over 50% of all xenobiotic metabolism.6 As such, it is a common epicenter for many frequently encountered drug interactions. CYP3A4 is thought to be the most important P450 enzyme due to its high capacity, abundance, and versatility.1 It accounts for 30% of the total liver P450 enzyme content7 and is so highly active that certain susceptible drugs can be 85% metabolized immediately following absorption, with only 15% of the drug molecules ever reaching their target organs.8 This so-called “first-pass metabolism effect” must be factored into the recommended dosages for CYP3A4-metabolized drug to ensure that the desired amount ultimately ends up in the blood stream.9 As a result, changing the activity of CYP3A4 can cause profound changes in the plasma levels of susceptible drugs in ways that can prove to be dangerous. Grapefruit juice is a highly notorious and prototypical inhibitor of this metabolic pathway and its ability to wreak havoc with drug concentrations is well-documented.5 Enzyme inhibitors are substances which are able to prevent the metabolic action of an enzyme. Considering that CYP3A4 is responsible for metabolizing opioids such as fentanyl and oxycodone, even modest amounts of CYP3A4 inhibitors taken with these drugs can have fatal outcomes.6 A single serving of grapefruit juice can increase the concentrations of the anti-anxiety drug buspirone (BuSpar) to 4.3 times what would normally be seen, causing a significant increase in the occurrence of adverse reactions.10 In addition to grapefruit juice, CYP3A4 is also strongly inhibited by drugs such as ritonavir, ketoconazole, itraconazole, erythromycin, clarithromycin, fluconazole, diltiazem, verapamil, and nefazodone. Many other drugs act as milder inhibitors of CYP3A4.
Inhibition is only one of two possible metabolic disturbances which can alter the concentrations of drugs in the human body. The polar opposite phenomenon is called induction and it can be equally problematic. Inhibition reduces the total amount of active enzyme present while induction increases it. This increases the rate of the associated reaction. Inhibitors hinder and disable enzyme molecules while inducers prompt the body to synthesize larger quantities of enzyme molecules. Each CYP450 enzyme is coded for by a unique gene.11 These genes are kept active at a precisely determined pace to maintain consistent metabolic activity. An inducer will cause the body to lay off its brakes controlling a certain enzyme’s expression and, as a result, more of that enzyme will be made. St. John’s Wort is a commonly encountered CYP3A4 inducer. One of its active components called hyperforin binds to a specialized receptor on the membrane of the cellular nucleus called the pregnane X receptor (PXR). One of the functions of CYP3A4 is to metabolize sex hormones including estrogen, testosterone, and progesterone.12 These hormones are able to bind to the PXR and when they do, the body increases its production of CYP3A4 and the hormones in question will be metabolized more rapidly.13 Therefore, the PXR creates a negative feedback loop which effectively places a “thermostat” on the hormonal system to maintain consistent levels of certain hormones. Any time these hormones rise above a certain level, the action of the PXR will accelerate their metabolism to bring the hormone concentrations back down into the normal range.12
Foreign inducers of CYP3A4 such as St. John’s Wort, phenytoin, carbamazepine, barbiturates, corticosteroids, and cafestol found in unfiltered coffee create false signals of hormone elevation by activating the PXR. As a result, the levels of all drugs metabolized by CYP3A4 will decrease when a CYP3A4 inducer is given. This can have significant consequences. Women on hormonal birth control pills can experience unexpected pregnancies when given St. John’s Wort, certain anti-seizure medications, and corticosteroids.14 That is because these drugs’ action on the PXR effectively defeats hormonal birth control. Individuals on steady doses of CYP3A4-reliant drugs can also experience withdrawal symptoms when exposed to CYP3A4 inducers. People dependent on benzodiazepines have experienced symptoms of benzodiazepine withdrawal when given St. John’s Wort. These issues can persist for quite some time as the newly synthesized enzyme molecules have the ability to linger in the body for several weeks. In addition to the PXR, several other nuclear receptors exist including the retinoid X receptor (RXR), the farnesoid X receptor (FXR), and the constitutive androstane receptor (CAR) which all have similar inductive effects on other CYP450 enzymes.15
So what does this all mean for individuals taking or tapering off of psychiatric medications? CYP3A4 is a very common metabolizer of many psychiatric medications. CYP3A4 metabolizes many antidepressants including citalopram, mirtazapine, trazodone, nefazodone, desvenlafaxine, reboxetine, and tricyclics like amitriptyline. CYP3A4 also metabolizes benzodiazepine and nonbenzodiazepine sedative-hypnotics and anxiolytics including alprazolam, triazolam, midazolam, clonazepam, diazepam, zolpidem, and buspirone as well as antipsychotics including quetiapine, aripiprazole, ziprasidone, lurasidone, and haloperidol. These are all referred to as CYP3A4 substrates due to their reliance on CYP3A4 for metabolism. In general, enzyme substrates require lower dosing in the presence of enzyme inhibitors and higher dosing in the presence of enzyme inducers. Patients should be aware if they are taking an inhibitor-substrate combination and be mindful of the fact that the two drugs are cooperating synergistically in the body. This requires more strategic dosing to avoid exaggerated side effects and also more strategic discontinuation protocols to avoid exaggerated withdrawal symptoms. A patient prescribed the CYP3A4 inhibitor nefazodone for depression and the CYP3A4 substrate alprazolam for anxiety should preferably taper off the alprazolam first and the nefazodone last. This is because any decreases in nefazodone levels will also decrease alprazolam levels as the metabolic inhibition is lifted. The patient is effectively dependent on the steady presence of both drugs to maintain steady alprazolam concentrations such that a reduction of either drug could result in benzodiazepine withdrawal symptoms. Tapering the alprazolam first is the only way to effectively eliminate one drug at a time. Tapering nefazodone first could result in compounded withdrawal symptoms as both the nefazdone and alprazolam levels will decline, potentially creating a hybrid of benzodiazepine withdrawal and antidepressant discontinuation syndrome. This instance is a notable exception of the typically recommended strategy of discontinuing antidepressants first and sedatives last.
In addition to CYP3A4, the enzymes CYP1A2, CYP2D6, and CYP2C19 are also common routes for the metabolism of psychiatric medications. CYP1A2 is a major degradation pathway for duloxetine, mirtazapine, agomelatine, clozapine, olanzapine, and tricyclic drugs to a lesser extent. It is also responsible for the metabolism of caffeine and it is inhibited by verapamil, fluvoxamine, ciprofloxacin, and peppermint oil. CYP1A2 can be induced by modafinil, tobacco smoke, broccoli, Brussels sprouts, cauliflower, and charred meat. CYP2D6 is responsible for the metabolism of fluoxetine, paroxetine, duloxetine, atomoxetine, venlafaxine, amphetamine, risperidone, aripiprazole, haloperidol, phenothiazines such as chlorpromazine, and tricyclics like amitriptyline. CYP2D6 is inhibited by fluoxetine, paroxetine, buproprion, quinidine, and ritonavir. It is induced by rifampin and corticosteroids. CYP2C19 is responsible for the metabolism of citalopram, moclobemide, diazepam, clonazepam, barbiturates, and tricyclics like amitriptyline. It is inhibited by proton pump inhibitor (PPI) antacids including omeprazole, lansoprazole, and pantoprazole and induced by rifampin, carbamazepine, norethindrone, and prednisone. Other CYP450 enzymes including CYP2B6 and CYP2C9 also play important roles in psychiatric drug metabolism. There are many other resources available which are able to expand upon the brief overview provided here.
It’s important to note that, in addition to the expansiveness of the entire metabolic scheme, there is a great deal of overlap, with certain drugs being equally metabolized by several different CYP450 enzymes and some drugs inhibiting or inducing several different CYP450 enzymes. Further complicating the issue is the fact that the entire P450 system is under genetic control such that differences in gene makeup will influence the activity of CYP450-mediated reactions. Many P450 enzymes are subject to genetic polymorphism in which some people are endowed with robust metabolic activity (so-called rapid metabolizers) and others have none at all.16 This means that not all drug interactions are relevant to every person. Different people will metabolize drugs differently and only genetic testing will be able to predict their metabolic trends.17 Obviously, the realm of drug interactions can be a very challenging territory for the average patient to navigate both during psychiatric treatment and throughout the tapering process. Here, pharmacists can often serve as valuable allies to help identify potential drug interactions and suggest methods to help mitigate them. That being said, one cannot assume that all pharmacists are fully aware of the information discussed here. Ideally that would be so, but if one fact should be abundantly clear to all victims of iatrogenic dependence, it is that the healthcare industry is riddled with informational gaps. Never make assumptions. Just because your pharmacist has denied the presence of an interaction in your regimen, do not assume that it is so. Take advantage of the many web-based drug interaction cross checking systems which have been made available to healthcare consumers as supplementary advisory tools. If you identify an interaction which your pharmacist overlooked, bring it to his or her attention. In some cases, certain documented interactions are too minor to be significant. Others need to be factored into the treatment regimens and tapering strategies. In most cases, your pharmacist will be able to discern which interactions are most relevant to you.
Brad Verret was biochemist and former medical student, who was employed at The Dow Chemical Company in polymer characterization. Brad’s benzodiazepine injury from Xanax began in 2011 as an undergraduate student. His health began to decline and he developed neurological symptoms consistent with multiple sclerosis. In 2014 Brad became aware of his tolerance to the drug, leading to being rapidly tapered off the drug in a week. After suffering a few agonizing months from the rapid withdrawal, he was reinstated and slowly tapered of Valium for a year, which was completed in August, 2016. Brad enjoyed using his free time to spread awareness of, and hope for those impacted by iatrogenic illness. Brad passed away in 2017.